Animal research on age-related cognitive deficits has typically focused on the impact of aging on specific learning tasks or domains. While informative regarding the brain substrates for task- specific (or even domain-specific) learning impairments, this approach provides little insight into the impact of aging on general cognitive/learning abilities. The prevailing focus on isolated tasks or domains has limited our understanding of "cognitive aging", as it has been estimated that 35-60% of age-related declines in cognitive performance are attributable to a diminishment of individuals'general cognitive ability, i.e., the capacity for cognitive performance that transcends the specific demands of any single task or domain. We have developed unique testing and analysis regimens that are sensitive to a general learning factor that accounts for >32% of the variance in the general cognitive performance of young adult laboratory mice. We have begun to apply this approach to studies of animals across the life span, and have isolated a general cognitive factor in 20 month old BALB-C mice that accounts for greater than 40% of the variance in the general cognitive abilities of these animals. While comparable in structure to that of young animals, in old animals this "general cognitive factor" consistently accounts for a greater proportion of the total variance in the cognitive performance of aged animals, suggesting that general cognitive abilities become increasingly dominant across the animal's life span. Moreover, we have established that in aged animals, general cognitive abilities become increasingly reliant on aspects of working memory, particularly, working memory span (resistance to decay) and working memory capacity (resistance to interference). Furthermore, general cognitive declines do not accrue homogeneously across the life span, such that some percentage of aged animals retain their cognitive abilities, while in others, these abilities decline rapidly, an effect associated with increasing body mass and decreases in general activity. We now hypothesize that the general cognitive decline in aged animals is the consequence of perturbations in the efficacy of the working memory system, including working memory span, capacity, and selective attention. We will test these possibilities in Aims 1 and 2, and in so doing, will gain critical insight into the processes that underlie age-related cognitive declines. It will then be possible in Aim 3 to test specific behavioral strategies (including manipulations of body weights, activity, and working memory efficacy) to innoculate animals against these declines, and possibly, to mitigate the progression of age-related declines that were previously instantiated. This work will provide a conceptually and empirically strong foundation for subsequent elucidation of the brain substrates for age-related cognitive impairments (as described in our Ancillary Aim), and ultimately, the development of strategies to overcome these impairments. PUBLIC HEALTH RELEVANCE: A critical need has emerged to develop strategies with which to treat the normal but pervasive cognitive impairments that are associated with aging. To do so, we must quantify the cognitive deficits associated with aging, understand the variability (i.e., individual differences) in the emergence of cognitive aging, and elucidate the psychological processes that underlie cognitive aging. The goal of this research program is to quantify cognitive declines across the life span, and to generate behavioral intervention strategies that facilitate the successful maintenance of cognitive abilities into old age.